JPH0529029B2 - - Google Patents

Abstract

Compounds of the formula:where R is an optionally substituted aryl or heteroaryl group;R¹ and R are each independently C₁-C₄ alkyl or 2-methoxyethyl; and Y is -(CH₂)_n- where n is 2, 3 or 4, -CH₂CH(CH₃)-or -CH₂C(CH₃)₂-; and their pharmaceutically acceptable salts.The compounds have utility as anti-ischaemic and antihypertensive agents and as synthetic intermediates to other dihydropyridine calcium antagonists.

Description

[Detailed description of the invention]

The present invention relates to certain dihydropyridines, particularly certain 1,4-dihydropyridines having a hydroxyl group or an oxo substituent in the side chain bonded to the 2-position, and which are useful as antiischemic and antihypertensive drugs and as synthetic intermediates. The compounds of the invention reduce the movement of calcium into cells, and therefore they can slow or prevent myocardial contraction that is thought to occur due to the accumulation of intracellular calcium in ischemic conditions. Excessive calcium influx during ischemia has a number of other adverse effects that may further compromise ischemic myocardium. These include reduced effective utilization of oxygen for ATP production, activation of fatty acid oxidation by mitochondria, and possibly enhanced cell necrosis. Accordingly, the compounds are useful in the treatment or prevention of various cardiac conditions, such as angina pectoris, cardiac arrhythmia, heart attack, and cardiac hypertrophy. The above compounds have a vasodilatory effect since they can prevent the influx of calcium into the cells of vascular tissue and are therefore useful as antihypertensive agents and also in the treatment of coronary vasospasm. According to the present invention, the following formula [In the formula, R is an optionally substituted aryl or heteroaryl; R ¹ and R ² are independently C ₁ -C ₄ alkyl or 2-methoxyethyl; Y is -(CH ₂ ) _o - (where n is 2, 3 or 4) _-CH2CH ( _CH3 )- or _CH2
(CH ₃ ) ₂ −. ] Novel 1,4-dihydropyridine derivatives and pharmaceutically acceptable salts thereof are provided. As used herein, the term "aryl" includes unsubstituted phenyl groups, as well as e.g., independently of each other, nitro, halo, _C1 - _C4 alkyl, _C1 - _C4
alkoxy, hydroxy, trifluoromethyl,
and a phenyl group substituted with one or two substituents selected from cyano. This also includes 1- and 2-naphthyl groups. "Halo" means F, Cl, Br or I. The term "heteroaryl" as used herein for R means an optionally substituted aromatic heterocyclic residue, such as a benzofuranyl group; a benzothienyl group; monosubstituted by methyl, thiomethyl, halo or cyano. pyridyl group, which may be -4-yl groups; and thienyl groups optionally monosubstituted with halo or _C1 - _C4 alkyl. Alkyl and alkoxy groups having 3 or more carbon atoms may be straight-chain or branched. R is preferably a phenyl group substituted with one or two substituents selected from halo and _CF3 , or a 2-chloropyrid-3-yl group. R is most preferably a 2-chlorophenyl group, a 2,3-diclophenyl group, a 2-chloro-3-trifluoromethylphenyl group, or a 2-chlorophenyl group.
It is a chloropyrid-3-yl group. Preferably R ¹ is CH ₃ and R ² is C ₂ H ₅ or R ¹ is C ₂ H ₅ and R ² is CH ₃ .
Most preferably R ¹ is CH ₃ and R ² is C ₂ H ₅ . Y is preferably −(CH ₂ ) ₂ −, −(CH ₂ ) ₄ −, −
_CH2CH ( _CH3 )- or _-CH2C ( _CH3 ) _2- . Formulas with one or more asymmetric centers ()
The compounds exist as one or more pairs of optical antipodes, and these pairs or individual isomers can be isolated by physical methods, such as fractional crystallization of the parent compound or of suitable derivatives thereof as will be apparent to those skilled in the art. It can be separated by chromatography or chromatography. The present invention includes each separated pair, as well as mixtures thereof (either as racemic mixtures or as separated optically active isomers). Compounds of the invention can be made by a number of routes, including those described below. (1) A compound of formula () in which Y is -(CH ₂ ) ₂ - can be produced by the following method. Ring closure is generally carried out by stirring dihydropyridine (), carbonyldiimidazole and N-methylmorpholine in a suitable organic solvent (eg, tetrahydrofuran) until the reaction is complete. The product () can then be collected by conventional methods. The reduction is then carried out by reducing the oxazine () with a suitable reducing agent in an organic solvent.
This can be carried out, for example, by reduction with sodium borohydride in ethanol at room temperature and with lithium aluminum hydride in tetrahydrofuran at about 0°C. If necessary, the reaction mixture can be heated to 80°C to accelerate the reaction. Isolate the product again,
It can be purified by conventional methods. Intermediates of formula () also form part of the invention. The starting materials of formula () are known compounds or can be prepared analogously to the prior art. See European Patent Application No. 0100189. Representative methods are as follows. (2) Y is −CH ₂ CH (CH ₃ )− or −CH ₂ C
A compound that is (CH ₃ ) ₂ − can be produced as follows. Reduction is generally carried out by reducing the ketone () with a suitable reducing agent in an organic solvent, such as sodium borohydride in ethanol at room temperature or lithium aluminum hydride in tetrahydrofuran at about 0°C. If necessary, the reaction mixture can be heated to about 80°C to accelerate the reaction. Product (B) can then be isolated by conventional methods. The reaction with methyllithium is generally carried out in an organic solvent (e.g. tetrahydrofuran) between -80 and 0.
Performed at ℃. Again the product (IC)
can be isolated by conventional methods. Ketones () can be produced from acids (). This process generally involves reacting an acid () and carbonyldiimidazole in, for example, dichloromethane to form an imidazolide. Reacting this with 2,2-dimethyl-1,3-dioxane-4,6-dione in the presence of pyridine, for example in dichloromethane,
The ketone is then obtained by hydrolysis under reflux, for example with aqueous acetic acid. These compounds and their pharmaceutically acceptable salts, which are useful as antiischemic and antihypertensive agents, form another aspect of the invention. (3) Y is -(CH ₂ ) _o - (where n is 2, 3 or 4
A compound which is ) can be prepared by reducing a suitable acid of the following formula. The preferred reducing agent is borane and the reaction is generally carried out in tetrahydrofuran. Temperatures from 0°C to room temperature are usually suitable, although heating up to 60°C can be used if necessary. The starting material () was synthesized by Haunchi synthesis [route (1)
Reference] It can be produced using an appropriately 4-substituted acetoacetate. (4) Y is -(CH ₂ ) _o - (where n is 2, 3 or 4
Compounds which are ) can also be produced by reduction of alkyl esters (). This reduction is preferably carried out using methyl or ethyl esters, in which case the preferred reducing agent is lithium aluminum hydride. Generally, the reaction is carried out in a suitable organic solvent (eg, tetrahydrophyrane) at temperatures from about 0°C to room temperature, although heating up to 60°C can be used if necessary. The starting material () can be produced by Hantzsch synthesis as in the case of formula (), and when n is 4,
A route via specific alkyne intermediates is used as detailed in the Preparation Examples below. This path can be diagrammed as below aqueous mineral acids (e.g. in aqueous dioxane)
H ₂ SO ₄ ) with the above alkynes and mercury ions (e.g. those derived from mercurous sulfate).
The reaction with is an alternative route to the ketone (). This reaction is generally carried out with moderate heating, for example between 50 and 70°C. The ability of compounds of formulas () and () to inhibit the movement of calcium into cellular cells is demonstrated by their potency in reducing the contraction of vascular tissue in vitro. This is the result of an influx of calcium caused by high extracellular concentrations of potassium ions. The test is performed by mounting a spirally cut rat aorta with one end fixed and the other end connected to a force transducer. The tissue is immersed in a saline bath containing 2.5mM Ca ² + and 5,9mM K. Potassium chloride is pipetted into the bath to give a final K concentration of 45mM and the change in tension caused by the resulting tissue contraction is recorded. The bath is drained and replaced with fresh saline and the test is repeated 45 minutes later with the specific test compound present in the saline. The concentration of compound required to reduce the response by 50% (IC ₅₀ ) is recorded. The antihypertensive activity of these compounds is assessed by measuring the reduction in blood pressure after oral administration in spontaneously hypertensive rats or renally hypertensive dogs. For administration to humans in the treatment or prevention of heart conditions and hypertension, the oral dosage of the compound is 5 to 100 mg for the average adult patient (70 kg).
mg/day, generally 10-60 mg/day. Thus, for the typical adult patient, an individual tablet or capsule will generally contain 5, 10 or 20 mg of active compound in a suitable pharmaceutically acceptable vehicle or carrier. Doses for intravenous administration will generally range from 1 to 10 mg/dose as required. In practice, the physician will determine the actual dosage that will be optimal for the individual patient. This will vary depending on the age, weight and response of the individual patient. The above dosages are exemplary of average cases, and there may, of course, be individual instances where higher or lower dosage ranges may be beneficial. These are also included within the scope of the present invention. For use in humans, the formulas () and ()
Although the compounds can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, alone or mixed with excipients, and also containing flavorings or colorants. It can be administered orally in the form of an elixir or suspension. They can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration,
It is best used in the form of a sterile aqueous solution which may contain other substances such as sufficient salts or glucose to make the solution isotonic. Accordingly, in another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula () or () or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. The present invention also includes compounds of formulas () and (), or pharmaceutically acceptable salts thereof, for use in medicine, particularly in the treatment of ischemic heart disease, angina or hypertension in humans. The invention consists of administering an effective amount of a compound of formula () or (), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above.
A method of protecting the heart from the deleterious effects of ischemia is also provided. The present invention includes an effective amount of a compound of formula () or () or a pharmaceutically acceptable salt thereof;
Alternatively, a method of treating hypertension by administering the above-described pharmaceutical composition is also included. In addition to being used as drugs, many of the compounds of formula
It has been found to be a useful synthetic intermediate as described in No. 8414520 (filed June 7, 1984). The application specification describes a dihydropyridine anti-ischemic drug and an antihypertensive drug of the following formula. In the above formula, R, R ¹ and R ² are as defined herein, and Y is -(CH ₂ ) _o - (where n is 2.3 or 4) or -CH ₂ CH (CH ₃ )
- and Het is an optionally substituted 5- or 6-membered member bonded to the adjacent oxygen atom by a carbon atom.
is a membered aromatic heterocyclic residue, and this heterocyclic residue may be fused to a benzene ring which may itself be substituted. A representative example of "Het" is an optionally substituted pyrimidinyl group. Generally, the preparation of a compound of formula () using the compound of the present invention is represented by the following formula. Compound () (i) Strong base (e.g. NaH) ――――――――――――――→ (ii) Het・Q compound () “Het” is as defined above. , Q is a leaving group, preferably Cl. The invention is illustrated by the following examples. All temperatures are in °C. Example 1 4-(2-chlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)
-5-methoxycarbonyl-6-methyl-1,
4-Dihydropyridine A 1M solution of borane in tetrahydrofuran (10
ml) in tetrahydrofuran (20 ml) as 2-{[4
-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,
4-dihydropyrid-2-yl]methoxy}acetic acid (2.0 g, see Preparation Example 4 of EP-A-0100189) was added to a stirred, ice-cooled solution for 10 min.
It was added dropwise over a period of minutes and the mixture was allowed to warm up to room temperature. The mixture was stirred at room temperature for 3 days and water (5
ml) and evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulphate and evaporated. The residual oil was purified by chromatography on silica gel (10 g) using hexane + 20→50% dichloromethane and then dichloromethane + 0→1% methanol as eluent. The appropriate fractions were combined and evaporated and the resulting oil was crystallized from hexane to give the title compound (0.6g).
Melting point 125-130°. 'H-nmr ( _CDCl3 , δ): 7.0-7.65 (5H,
m); 5.48 (1H, s); 4.81 (2H, s); 4.12 (2H,
q, F=7Hz); 3.5-4.0 (4H, m); 3.65 (3H,
s); 2.38 (3H, s) and 1.21 (3H, t, J=7
Hz). Example 2 4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine 2-{[4-(2 ,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (European Patent Application Publication No.
The title compound was prepared by the method described in Example 1 using 0100189, Example 5) and borane as starting materials. The product had a melting point of 120-121°. Elemental analysis (%): Actual value: C, 54.30; H, 5.49; N, 3.13 C ₂₀ H ₂₃ Cl ₂ NO ₆ Theoretical value: C, 54.06; H, 5.22; N, 3.15 Example 3 (A) 7- (2,3-dichlorophenyl)-8-ethoxycarbonyl-6-methoxycarbonyl-5
-Methyl-3-oxo-2,3,7,9-tetrahydropyrido[1,2-c]-1,4-oxazine 2-{[4-
(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (9.16 g), carbonyldiimidazole (3.60 g) and N- A solution of methylmorpholine (3.5ml) was stirred at room temperature for 16 hours and then evaporated. The residue was taken up in diclmethane and the solution was washed with 2M hydrochloric acid, 10% aqueous sodium bicarbonate and water, dried over _Na2SO ,
Evaporated. The residue was recrystallized from ethyl acetate to obtain the title compound (4.70 g). Melting point 172-173°. Elemental analysis: Actual value: C, 53.27; H, 4.27; 3.15 _C20H19Cl2NO6 Theoretical value _: C, 53.27; H, 4.44; _N , 3.27 (B) 4-(2,3 _- dichlorophenyl)- 3-Ethoxycarbonyl-2-(2-hydroxyethoxymethyl)-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine Sodium borohydride (1.52 g) and 7-(2,3 -dichlorophenyl)-8-ethoxycarbonyl-6-
Methoxycarbonyl-5-methyl-3-oxo-2,3,7,9-tetrahydropyrido [1,
A mixture of 2-c]-1,4-oxazine (9.00 g) was stirred at room temperature for 16 hours and then evaporated. The residue was taken up in dichloromethane and the solution was washed with water, 2M hydrochloric acid and water, dried over sodium sulphate and evaporated. The residue was crystallized from ether to give the title compound (6.00g).
Melting point 120-121°. This substance was determined by spectroscopic analysis.
It was confirmed that it was the same as that obtained by the method of Example 2. Examples 4 and 5 The following compounds were prepared analogously to the methods of Examples Parts A and B above from the corresponding starting materials below.

[Table] Substituted acetic acid-based starting materials, i.e. 2-
{[4-(2-chloro-3-trifluoromethylphenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (melting point 168°C ~
70°) and its 4-(2-chloropyrid-3-yl) homolog (isolated as a foam) were prepared analogously to the method of Example 4 of EP-A-0100189. These were used as is. Example 6 (A) 1-{[4-(2,3-dichlorophenyl)-3
-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2
Carbonyl diimidazole (8.00 ml) in dichloromethane (400 ml)
g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetic acid (20.00 g)
A solution of was stirred at room temperature under nitrogen for 2 hours, then pyridine (3.60 g) in dichloromethane and 2,2-dimethyl-1,3-dioxane-4,
Added to a solution of 6-dione (6.50 g) over 5 minutes. The mixture was stirred at room temperature for 2 days, washed successively with ice-cold 2.5M hydrochloric acid and saturated brine, dried over magnesium sulfate and evaporated. The residue was dissolved in water (300ml) and acetic acid (150ml) and refluxed for 5 hours. Evaporate the mixture;
Partitioned between diethyl ether (800ml) and 10% aqueous sodium carbonate. The ether solution was dried over magnesium sulphate and evaporated. The residue was dissolved on “Kieselgel 60-H”™ silica (50 g) in dichloromethane for 30 min.
% hexane. Fractions containing pure product were evaporated to give the title compound (6.5g). Melting point 117-119°. Elemental analysis (%): Actual value: C, 55.41; H, 5.17; N, 3.46 C ₂₁ H ₂₃ Cl ₂ NO ₆ Theoretical value: C, 55.27; H, 5.08; N, 3.07 (B) 1-{[4 -(2,3-dichlorophenyl)-3
-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2
-yl]methoxy}propan-2-ol 1-{[4-(2,3
-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
A solution of 1,4-dihydropyrid-2-yl]methoxy}acetone (0.46 g) and sodium borohydride (0.10 g) was stirred at room temperature for 5 hours. The solution was evaporated and the residue was dissolved in ethyl acetate and washed three times with water. The organic layer was dried over magnesium sulphate and evaporated. The residue was crystallized from diethyl ether/hexane to give the title compound (0.20g). Melting point 110-113°. Elemental analysis (%): Actual value: C, 55.01; H, 5.36; N, 3.09 C ₂₁ H ₂₅ Cl ₂ NO ₆ Theoretical value: C, 55.03; H, 5.50; N, 3.06 Example 7 1-{[4 -(2,3-diclophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyrid-2-yl]methoxy}acetone 1-{[4-(2,3-dichlorophenyl)-3 in a mixture of water (20 ml) and dioxane (20 ml)
-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (1.06 g) [see Preparation Example 3], mercurous sulfate (0.10 g) and concentrated A solution of sulfuric acid (0.2ml) was heated at 60° for 2 hours and then evaporated. The residue was partitioned between ether and water and the organic layer was washed with saturated aqueous sodium chloride and water, dried over sodium sulphate and evaporated to give the title compound (0.93g). Melting point 119-121°.
This material was confirmed by spectroscopic analysis to be identical to the product of Example 6(A). Example 8 4-{[4-(2,3-diclophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-
6-Methyl-1,4-dihydropyrid-2-yl]methoxy}-1-hydroxybutane 4-{[4-
(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-
1,4-dihydropyrid-2-yl]methoxy}
A solution of methyl butanoate (0.50 g) was added dropwise over 10 minutes to a stirred, ice-cooled suspension of lithium aluminum hydride (76 mg) in tetrahydrofuran (25 ml). The mixture was stirred at 0° for 70 min, quenched by pouring into excess ice water and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed twice with water, dried (magnesium sulphate) and evaporated. The residue was purified by chromatography on silica (7 g) using dichloromethane + 0→20% (v/v) ethyl acetate as eluent. The appropriate fractions were combined and evaporated and the residue was recrystallized from diisopropyl ether to give the title compound (0.28g). Melting point 103-104°. Elemental analysis (%): Actual value: C, 55.82; H, 5.77; N, 3.34 C ₂₂ H ₂₇ Cl ₂ NO ₆ Theoretical value: C, 55.93; H, 5.72; N, 2.97 Example 9 1-{[4 -(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2-
yl]methoxy}-2-hydroxy-2-methylpropane. 1/2 hydrate 1.6M methyllithium solution in ether (1.3
ml) in tetrahydrofuran (30 ml).
{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetone (0.46 g) (see Example 6) The solution was added dropwise over 5 minutes with stirring and cooling in an isopropanol/solid carbon dioxide bath. The mixture was stirred with cooling for 30 minutes, warmed to 0°, and then stirred at 0° for 20 minutes. The reaction mixture was quenched by pouring it into saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and evaporated. The residue was purified by chromatography on SiO ₂ (6 g) using toluene + 0→50% (v/v) ethyl acetate as eluent. The appropriate fractions were combined and evaporated and the residue was recrystallized from diisopropyl ether to give the title compound (0.14
g) was obtained. Melting point 142−143°. Elemental analysis (%): Actual value: C, 55.12; H, 5.64; N, 2.91 C ₂₂ H ₂₅ Cl ₂ NO ₆ .0.5H ₂ O Theoretical value: C, 55.11; H, 5.43; N, 2.92 Example 10 This example illustrates the use of the product of Example 1 as a synthetic intermediate and is similar to Example 1 of the Applicant's UK Patent Application No. 8414520. 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-
Methyl-2-[2-(2-pyrimidinyloxy)ethoxymethyl]-1,4-dihydropyridine Sodium hydride (80% by weight dispersion in oil90
mg) in tetrahydrofuran (20 ml).
-chlorophenyl)-3-ethoxycarbonyl-
was added to a solution of 2-(2-hydroxyethoxymethyl)-3-methoxycarbonyl-6-methyl-1,4-dihydropyridine (0.60 g) and the mixture was stirred at room temperature for 45 minutes, then 2-chloropyrimidine (0.17 g). The mixture was stirred at room temperature for 3 days and evaporated. Dissolve the residue in ethyl acetate,
The solution was washed successively with 2M hydrochloric acid, 5% aqueous sodium carbonate, and brine, dried over magnesium sulfate, and evaporated. The residue was crystallized from ether to give the title compound (90mg). Melting point 101°. Elemental analysis (%): Observed: C, 58.77; H, 5.52; N, 8.50 _{C24H26ClN3O6 Theoretical} : C, _59.07 ; H, _5.37 ; N, 8.61 The following production example is based on a specific starting point. This explains the production of the substance. All temperatures are in °C. Production example 1 4-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2-
Methyl]methoxy}butanoate 4-{[4-(2,3-
dichlorophenyl)-3-ethoxycarbonyl-
5-methoxycarbonyl-6-methyl-1,4-
Dihydropyrid-2-ylmethoxy}butyne(2)
A solution of methyl acid (1.00g) was heated to 1 atm (1.0333Kg・
cm ⁻² ) of hydrogen at room temperature in the presence of 5% palladium on barium sulfate. Once hydrogen uptake had stopped, the mixture was filtered and evaporated. The residue was purified by chromatography on silica (6 g) using toluene + 0→50% ethyl acetate as eluent. Combine and evaporate the appropriate fractions,
The residue was crystallized from diisopropyl ether to give the title compound (0.40g). Melting point 78−80°. Elemental analysis (%): Actual value: C, 55.32; H, 5.42; N, 2.80 C ₂₃ H ₂₇ Cl ₂ NO ₇ Theoretical value: C, 55.42; H, 5.42; N, 2.81 Production example 2 4-{[4 -(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2-
Methyl]methoxy}butyno(2)ate A 1.6 M n-butyllithium solution (45 ml) in hexane was dissolved in 1.6 M n-butyllithium solution (45 ml) in 1.
-{[4-(2,3-diclophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (132 g) in a solution of It was added dropwise while keeping the temperature below -40°. The mixture was stirred at -60° for 2 hours, then carbon dioxide gas was added to the solution with cooling in an acetone/solid carbon dioxide bath for 30 minutes.
Conducted for minutes. The mixture was warmed to 0° while continuing to pass carbon dioxide gas, then it was quenched with water (1) and the layers were separated. The aqueous layer was extracted into ether (500ml) and the combined organic layers were washed with water, diluted with dichloromethane, washed with 1M hydrochloric acid, dried over magnesium sulphate and evaporated. The residue was triturated with methanol and the resulting solid was collected, washed with cold (-20°) methanol and dried to give 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl- 5-Methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}butyric acid (83.7
g) was obtained. Melting point 150-152°. This crude acid (14g) in methanol (100ml)
and concentrated hydrochloric acid (1 ml) was heated under reflux for 2 hours, concentrated to a volume of 50 ml and diluted with water (140 ml) and chloroform (140 ml). The layers were separated and the organic layer was washed with water, dried _{over Na2SO4} and evaporated. Triturate the residue with hot methanol, collect the resulting solid after cooling, wash with methanol,
Drying gave the title ester (9.0g).
Melting point 111−113°. Production example 3 1-{[4-(2,3-dichlorophenyl)-3-
Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrido-2-
yl]methoxy}-2-propyne Piperidine (2.4g) is mixed with isopropanol (600g).
ml) of ethyl 4-(propyl(2)-oxy)acetoacetate (63 g) and 2,3-dichlorobenzaldehyde (60 g) under stirring over a period of 10 minutes and the mixture was stirred at room temperature. Stirred for 24 hours.
The mixture was then diluted with methyl 3-aminocrotonate (39
g), stirred for 4 days at room temperature and evaporated. Dissolve the remaining oil in methanol (300ml),
The solution was kept at -20° for 2 days. The resulting solid was collected, washed with cold methanol and dried to give the title compound (29.5g). Melting point 104−105°. I used this as is. Production example 4 Ethyl 4-(propyl-(2)-oxy)acetoacetate ClCH ₂ COCH ₂ COOC ₂ H ₅ +CH≡C.CH ₂ OHNaH ---→ THF.CH≡C.CH ₂ OCH ₂ COCH ₂ COOC ₂ A solution of ethyl 4-chloroacetoacetate (294 g) in _H5 tetrahydrofuran (200 ml) was stirred for 3 hours and cooled on ice. The reaction temperature was 20°
was added at a rate that was maintained at . Then propyn(2)-ol (100 ml) in tetrahydrofuran (200 ml)
The solution of g) was added to the above mixture over a period of 2 hours under stirring and ice cooling at such a rate that the reaction temperature never exceeded +25°. The mixture was then stirred at room temperature for 16 hours, poured into 2M hydrochloric acid (900ml) and the layers were separated. The organic layer was evaporated and the resulting oil was separated from the mineral oil in a separatory funnel. The red oil was taken up in dichloromethane and the resulting solution was washed several times with water, dried over sodium sulphate and evaporated to give the title compound (313g) as a black oil. This was used as it was in Production Example 3.

[Claims]

1 General formula [In the formula, Ar is a 3-nitrophenyl group or 2,3
- Dichlorophenyl group, A has 2 to 6 carbon atoms
represents a straight-chain or branched alkylene group, and R represents a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which may be mono-substituted with an alkoxy group having 1 to 6 carbon atoms. and R ₁ represents an alkyl group having 1 to 4 carbon atoms. ] 1,4-dihydro-2,6-dimethyl-3-(alkoxycarbonyl or alkoxyalkoxycarbonyl)-4-(substituted phenyl)-

Claims (1)

salt. 2 R is a phenyl group substituted with 1 or 2 halogen atoms, or 2-chloropyrido-
The compound according to claim 1, which is a 3-yl group. 3. The compound according to claim 2, wherein R is a 2-chlorophenyl group or a 2,3-dichlorophenyl group. 4. The compound according to claim 2, wherein R is a 2-chloro-3-trifluoromethylphenyl group or a 2-chloropyrid-3-yl group. 5 Y is -(CH ₂ ) ₂ -, -(CH ₂ ) ₄ -, -CH ₂ CH
The compound according to any one of claims 1 to 4, which is ( _CH3 )- or _-CH2C ( _CH3 ) _2- . 6 Any one of claims 1 to 5, wherein R ¹ is a methyl group and R ² is an ethyl group
Compounds described in Section.